Origin of inherited pain disorder pinpointed

The genetic basis for a rare inherited disorder that causes severe burning pain with no warning has been pinpointed by researchers. They found that paroxysmal extreme pain disorder (PEPD) is caused by specific mutations in porelike sodium channels in peripheral nerve cells—a discovery that they said emphasizes the role of such channel disorders in inflammatory pain. Such findings of abnormal function in disease also provide insights into the normal function of such channels, they said.

R. Mark Gardiner, of University College London, and his colleagues published their findings in the December 7, 2006, issue of the journal Neuron, published by Cell Press.

So-called "voltage-gated sodium channels" are central to the neuron's ability to propagate a nerve impulse. In response to voltage changes in a nerve cell caused by a nerve impulse, these channels snap open, allowing sodium to flow across the cell membrane, further propagating the nerve impulse. Rapid, precise activation and inactivation is key to their normal operation.

In their studies, the researchers sought to understand the basis of PEPD, which is characterized by abrupt paroxysms of pain in the rectum, eye, and jaw. They first performed a detailed genetic comparison of affected and unaffected members of one large family that showed inheritance of the disease. That analysis revealed that mutations that compromise the gene for a component of one particular sodium channel, called SCN9A, were the likely culprit. Further analysis of the gene in 11 affected families and two sporadic cases, indeed, revealed that mutations in SCN9A are responsible for the disease in at least two-thirds of PEPD cases.

Analysis of these mutations revealed that they all disrupted the ability of the sodium channel to rapidly snap shut, prolonging activation of the peripheral nerves in which the channels functioned. What's more, the researchers found, the drug carbamazepine—known to be effective in PEPD—acts to correct this abnormality in cultures of neurons.

The researchers also compared PEPD with another inherited pain disorder, primary erythermalgia (PE) that is not alleviated by carbamazepine. PE is also caused by mutations in SCN9A and is characterized by pain in the extremities triggered by exercise or temperature change. In contrast to PEPD, which is caused by mutations that disrupt inactivation the sodium channel, PE arises from mutations that lower its activation threshold.

The researchers concluded that their findings "further emphasize the critical role of [this sodium channel] in human inflammatory pain and explain the differential drug sensitivity of PEPD and PE."

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The researchers include Caroline R. Fertleman, Keith A. Parker, Sarah Moffatt, Frances V. Elmslie, R. Mark Gardiner, and Michele Rees of Royal Free and University College Medical School, University College London in London, UK; Mark D. Baker, Bjarke Abrahamsen, and John N. Wood of University College London in London, UK; Johan Ostman of Queen Mary's School of Medicine and Dentistry in London, UK; Norbert Klugbauer of Albert-Ludwigs-Universität Freiburg in Freiburg, Germany.

This work was funded by The Wellcome Trust (Research Training Fellowship, C.R.F.) and MRC (UK).